A few months ago, I looked at the issue of opioid and other pain medication abuse (Drug war: FDA and Pharma vs. opioid abusers) and what avenues some companies are exploring in order to counter the epidemic of drug abuse. Efforts vary from adjusting the physical properties to make it impossible for the drug to be mixed for injection or crushed for inhalation, adding molecules that inhibit release of the drugs until they enter the intestines through proper oral administration, or creating agonist-antagonist combinations.

And another method is that taken by Nektar Therapeutics, which is working on a more chemical approach by attaching a polymer to the opiate to slow the speed at which the drug moves across the blood-brain barrier. In its compound, NKTR-181, there is no way of forcing the pain medication to release more quickly, maintaining the usual slow-release method and blocking abuse. In an interview with Dr. Rob Medve, chief medical officer of Nektar, we got a deeper look at this method and its possible potential in other venues.

ddn: How are NKTR-181’s features different from other approaches to abuse resistance in pain medicines?

Medve: Abuse of prescription medications, including opioids, has become a serious public health issue, creating a problem needing a solution, or in other words, an opportunity for innovation. A variety of approaches have been used to solve this problem but all of them involve some physical barrier to accelerated delivery of the active ingredient, most often oxycodone. The challenge with these physical barriers is that abusers, of course, have found ways to crush, melt, or otherwise manipulate these drugs to abuse them.

NKTR-181 is fundamentally different…because we’ve created a brand-new opioid structure using polymer drug conjugate technology. As a result, the properties of NKTR-181 are inherent to its molecular structure and crushing, melting or manipulating it won’t change those properties. As evidence of that, when NKTR-181 is administered as an oral liquid in our early human studies, the peak drug level occurs within two to four hours (as opposed to under an hour for immediate release oxycodone tablets).  We have used no specialized formulation to achieve this slower peak in the plasma, it is simply inherent to NKTR-181’s design.

Importantly, once in the body, highly abused drugs like oxycodone cross into the brain rapidly at high levels causing euphoria that can lead to abuse—but NKTR-181 is specifically designed to cross slowly into the brain and we see this reflected even in our first human clinical study. When we track the central effect of NKTR-181 through pupillometry, which measures pupil miosis that occurs with activation of opioid receptors in the brain, we observe that the time course of NKTR-181’s central effect lags behind its blood levels. While NKTR-181 achieves peak blood levels within 2 to 4 hours, its peak central effect as measured by pupillometry occurs later, peaking at 4 to 6 hours…demonstrating its slow rate of entry into the brain.

ddn: How much safer does NKTR-181′s characteristics make it in terms of increasing its abuse resistance?

Medve: The most commonly and highly abused drugs—cocaine, nicotine, oxycodone, etc.—all share a common element: speed. These are substances that enter the bloodstream quickly and then rapidly and extensively enter the brain and once there trigger the release of dopamine, the “pleasure chemical.”  A common pattern often apparent in abusers is seeking faster and faster onset: first taking intact drug, then crushing it and dissolving in alcohol, then snorting it and then injecting it—always chasing the rush , the speed of onset, that surge of dopamine in the brain. On a very simple level, the NKTR-181 molecule itself doesn’t “want” to enter the brain quickly because of the unique technology we’ve incorporated into the molecule. In clinical terms, that means less incentive to use the drug again—and if its onset can’t be made faster, then it is less attractive for abuse.

ddn: Given how NKTR-181 can slow its entry into the central nervous system, do you think its method of effectively controlling how it moves across the blood brain barrier could be extrapolated into other therapeutics?

Medve: We believe Nektar’s technology has enormous potential. We know we can modify the distribution of drugs within the body and as our depth of understanding of the technology increases, the potential applications increase. Pain is an obvious target and so even within pain there are many ways we can apply our technology to improve care—you will definitely see more from us in this area. In addition to controlling how drugs cross the blood brain barrier, we are discovering how our technology can potentially allow us to control the crossing of other membrane barriers within the body and allow us to compartmentalize drugs in desired areas of the body. This opens up opportunities for us to pursue new research candidates in many different therapeutic areas.

ddn: What do you think future efforts might consist of as experts and researchers in the field of pain medication move forward and continue to deal with the issue of opioid/pain medication abuse?

Medve: The “Holy Grail” of pain management has always been opioid efficacy without opioid side effects. The fact is that opioids work really well; in fact, they are the gold standard for analgesia. Even though opioids have been around for literally thousands of years (since the juice of the poppy), we are still evolving our understanding of everything they do and how. New methods allow us to see different types of receptors, to see how drugs fit into those receptors, to see where those receptors are in the body and what can be achieved by being selective in what is activated and when. There is a lot of research on other receptors systems other than opioid receptors, or working on ion channels and so forth. Some of these approaches may have utility for some types of pain, but mu-opioid agonists have broad utility in all types of pain. We believe the future is and should be focused on capturing the benefits of opioids while tuning out their risks with novel drug design—not just the same old formulations.